Loss of PTEN expression by blocking nuclear translocation of EGR1 in gefitinib-resistant lung cancer cells harboring epidermal growth factor receptor-activating mutations
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Abstract
Gefitinib (Iressa) and erlotinib (Tarceva), which target the epidermal growth factor receptor (EGFR), are approved for treatment of patients with advanced non-small cell lung cancer (NSCLC). Patients whose tumors harbor mutations in the EGFR gene, including delE746-A750 in exon 19 and L858R in exon 21, may benefit in particular from gefitinib treatment. However, acquired resistance to gefitinib has been a serious clinical problem, and further optimization is needed for application of EGFR-targeted drugs in lung cancer patients. In this study, we established gefitinib-resistant NSCLC cells from PC-9 cell line, which harbors the delE746-A750 mutation, by exposing the cell line to gefitinib for over 7 months. Gefitinib-resistant PC-9/GEFs cell lines showed a marked downregulation of PTEN expression and increased Akt phosphorylation. In revertant, gefitinib-sensitive clones (PC-9/Rev) derived from PC-9/GEF1-1 and PC-9/GEF2-1, PTEN expression, as well as sensitivity to gefitinib and erlotinib, was restored. Knockdown of PTEN expression using small interfering RNA specific for PTEN in PC-9 cells resulted in drug resistance to gefitinib and erlotinib. Nuclear translocation of the EGR1 transcription factor, which regulates PTEN expression, was shown to be suppressed in resistant clones and restored in their revertant clones. Reduced PTEN expression was also seen in tumor samples from a patient with gefitinib-refractory NSCLC. This study thus strongly suggests that loss of PTEN expression contributes to gefitinib and erlotinib resistance in NSCLC. Our findings reinforce the therapeutic importance of PTEN expression in the treatment of NSCLC with EGFR-targeted drugs.
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Because PI3K signaling lies downstream of EGFR, PTEN inactivation probably contributes to progression or therapeutic resistance in EGFR-TKI-treated patients.
“Given that the PI3K pathway is downstream of the EGFR-signaling pathway, it is likely that PTEN inactivation plays an important role in progression and/or therapeutic resistance in patients treated with EGFR-TKIs.23”
From Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC (2019) · cites this paper as [23]
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- Authors
- Yamamoto, C., Basaki, Y., Kawahara, A., Nakashima, K., Kage, M., Izumi, H., Kohno, K., Uramoto, H., Yasumoto, K., Kuwano, M., & Ono, M.
- Affiliations
- Kurume University (JP)
- Venue
- Cancer Research
- Published
- 2010-10-31
- Volume
- 70
- Issue
- 21
- Pages
- 8715-8725
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2141552280
- Cited by
- 155
- References
- 44
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 6 · 2020: 9 · 2019: 8 · 2018: 16 · 2017: 15 · 2016: 12 · 2015: 17 · 2014: 10 · 2013: 16 · 2012: 17
- FWCI
- 11.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (21591831)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- gefitinib resistance, erlotinib resistance, PTEN, EGR1, nuclear translocation, non-small cell lung cancer, EGFR mutation, exon 19 deletion, L858R mutation, Akt phosphorylation, anti-EGFR therapy, PC9 cells, transcriptional regulation
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Carcinoma, Non-Small-Cell Lung, Cell Nucleus, Humans, Immunoenzyme Techniques, Lung Neoplasms, Mutation, Phosphorylation, Quinazolines, RNA, Messenger, Tumor Cells, Cultured, Blotting, Western, Drug Resistance, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction, Protein Transport, RNA, Small Interfering, Protein Kinase Inhibitors, Cell Proliferation, PTEN Phosphohydrolase, Early Growth Response Protein 1, ErbB Receptors
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